ABSTRACT Tuberculous meningitis (TBM) arises when Mycobacterium tuberculosis (Mtb) crosses the blood-brain barrier (BBB), and is the most lethal and disabling form of tuberculosis (TB). In some patient populations, including HIV patients, TBM mortality approaches 50% despite therapy, and long-term disability is very common amongst survivors due to permanent brain injuries. These injuries are induced in large part by tissue damaging immune responses and by metabolic disturbance leading to neurotoxic and degenerative neurological damage. This project is based on our hypothesis that poor clinical outcomes in TBM are due to tissue damaging inflammation, the lack of adequate therapies that dampen counterproductive host responses, and inadequate antibiotic penetration into central nervous system (CNS) lesions. We propose an integrated program of translational and clinical research to develop and validate tools, biomarkers and models, which will help predict disease-induced disability, quantify drug penetration at the site of disease, characterize disease progression, and model response to therapy. The program combines multi- omic, pharmacokinetic and drug-drug interaction analyses of clinical trial samples, with investigations of pathogenesis, drug penetration at the site of disease, and testing of novel treatments in a rabbit model of TBM disease. The clinical -omics signatures will not only generate predictors of death and disability, but also guide optimization of the rabbit model. The project will draw from two separately funded Phase IIA and Phase III trials (LASER-TBM and INTENSE-TBM, respectively) in South Africa, evaluating the safety and efficacy of enhanced antimicrobial and host-directed therapy, including antibiotics approved for TB (high dose rifampicin added to standard of care) and repurposed drugs (linezolid and aspirin), for adults with TBM. We will use the optimized rabbit model of TBM to measure the CNS lesion penetration of TB-specific and repurposed antibiotics and of novel agents. If adequate CNS penetration is demonstrated, the pathogen- and host-directed activity of these drugs will be further evaluated in the rabbit model. Using these outputs, we will build a translational model integrating clinical and rabbit site-of-disease PK-PD data to define the contribution of therapeutic interventions on efficacy endpoints in clinical trials, and to define PK-PD targets for antitubercular therapy in TBM. The results of these integrated approaches will be forward-translated to propose evidence-based drug regimens with the potential to improve on death rate and neuro-disability. The principal investigators and their teams combine basic, translational and clinical research at four institutions with expertise in multi-omics analyses, pharmacology and immunobiology.